Heme oxygenase-1 gene transfer inhibits inducible nitric oxide synthase expression and protects genetically fat Zucker rat livers from ischemia-reperfusion injury
Heme oxygenase-1 gene transfer inhibits inducible nitric oxide synthase expression and protects genetically fat Zucker rat livers from ischemia-reperfusion injury
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DOI：
10.1097/00007890-200207150-00017
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发表时间：
2002-07-15
期刊：
影响因子：
6.2
通讯作者：
Kupiec-Weglinski, JW
中科院分区：
文献类型：
--
作者：
Coito, AJ;Buelow, R;Kupiec-Weglinski, JW
背景。缺血/再灌注（I/R）损伤是脂肪变性原位肝移植功能障碍的重要因素。血红素加氧酶-1 （HO-1）是一种细胞保护蛋白，可能在改善肝I/R损伤中起重要作用。我们使用腺病毒（Ad）为基础的HO-1基因转移来分析HO-1过表达对肥胖Zucker大鼠的影响。原位肝移植后I/R模型。与未经治疗和使用Ad-(3-半乳糖苷酶（Ad-(3-Gal)）治疗的肝脏相比，Ad- ho -1基因治疗提高了受体的存活率（80%，对照组为40-50%），并显著减少了肝细胞损伤。与对照组相比，原位肝移植Ad-HO-1组门静脉区巨噬细胞浸润较少。与未经治疗和ad - β - gal处理的原位肝移植对照组不同，诱导型一氧化氮合酶水平通过浸润巨噬细胞而升高，Ad-HO-1组几乎没有诱导型一氧化氮合酶的表达。相比之下，内皮一氧化氮合酶在Ad-HO-1和ad - β - gal转导的脂肪原位肝移植中具有可比性。与ad - β - gal对照组相比，ad - ho -1处理的原位肝移植细胞中抗凋亡Bcl-2和Bag-1的表达增加。此外，HO酶活性的升高伴随着caspase-3蛋白表达的抑制。HO-1基因的转移可显著延长脂肪变性原位肝移植的生存期，抑制巨噬细胞浸润，抑制诱导型一氧化氮合酶的局部表达，调节促凋亡和抗凋亡通路。
Background. Ischemia/reperfusion (I/R) injury is a critical factor in the dysfunction of steatotic orthotopic liver transplants. Heme oxygenase-1 (HO-1), a cytoprotective protein, may be important in ameliorating hepatic I/R injury.Methods. We used adenovirus (Ad)-based HO-1 gene transfer to analyze the effects of HO-1 overexpression in a well-established fatty Zucker rat. model of I/R followed by orthotopic liver transplantation.Results. Ad-HO-1 gene therapy increased recipient survival (80% vs. 40-50% in controls) and significantly diminished hepatocyte injury, as compared with untreated and Ad-(3-galactosidase (Ad-(3-Gal)-treated livers. Orthotopic liver transplants in the Ad-HO-1 group exhibited less macrophage infiltration in the portal areas, as compared with controls. Unlike untreated and Ad-beta-Gal-treated orthotopie liver transplant controls, which showed elevated levels of inducible nitric oxide synthase by infiltrating macrophages, inducible nitric oxide synthase expression in the Ad-HO-1 group was almost absent. In contrast, endothelial nitric oxide synthase was comparable in Ad-HO-1- and Ad-beta-Gal-transduced fatty orthotopic liver transplants. Intragraft expression of antiapoptotic Bcl-2 and Bag-1 was increased in Ad-HO-1-treated orthotopic liver transplants, as compared with Ad-beta-Gal controls. Moreover, increased HO enzymatic activity was accompanied by inhibition of caspase-3 protein expression.Conclusions. HO-1 gene transfer significantly prolongs survival of steatotic orthotopic liver transplants, depresses macrophage infiltration, suppresses local expression of inducible nitric oxide synthase, and modulates pro- and antiapoptotic pathways.